1. Field of the Invention
This invention relates to a process for preparing 2-thio-2-substituted-alkanoic acid derivatives represented by the formula (I) ##STR3## wherein A represents (1) a substituted-phenyl group of the formula ##STR4## in which Y.sup.1 represents an unsubstituted or substituted-phenoxy group wherein the substituent is a halogen atom, a trifluoromethyl group or an alkoxy group having 1 to 4 carbon atoms, or (2) a substituted-thienyl group of the formula ##STR5## in which Y.sup.2 represents an alkyl group having 1 to 4 carbon atoms; R represents an alkyl group having 1 to 4 carbon atoms; R.sup.3 represents a phenyl group, an alkylphenyl group wherein the alkyl group has 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms; and R.sup.4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, which are useful as intermediates for the synthesis of various pharmaceutical agents.
2. Describtion of the Prior Art
Hitherto, salicyclic acid derivatives, pyrazolone derivatives, indomethacin, etc. have been used widely as anti-inflammatory agents. These agents generally exhibit a potent anti-inflammatory activity, but they also tend to cause serious side-effects such as gastro-intestinal disorders, adverse affects on hematosis, etc. upon administration.
Recently, various alkanoic acid derivatives such as 2-(3-phenoxyphenyl)alkanoic acid compounds have been interesting because of their low possibility of causing side-effects, while the anti-inflammatory activity thereof is not so potent, thereby making it possible to administer these agents over a prolonged period of time to patients.
The compounds of the formula (I) wherein A represents a 3-phenoxyphenyl group can be easily converted into the above 2-(3-phenoxyphenyl)alkanoic acid compounds. Also, the compounds of the formula (I) wherein A represents a substituted-thienyl group can be easily converted, upon reduction, into an .alpha.-(2-thienyl)alkanoic acid which can then be converted into thiobrophenic acid having an anti-inflammatory activity, as disclosed in Japanese Patent Publication (Examined) No. 24915/74. Further some esters of the above .alpha.-(2-thienyl)alkanoic acid are known to have a high insecticidal activity, as disclosed in Japanese Patent Publication (Unexamined) No. 126826/74.
Typical conventional processes for preparing 2-(phenoxyphenyl)alkanoic acid derivatives represented by the formula (I) wherein A represents a substituted-phenyl group includes (1) a process comprising heat-refluxing a 3-phenoxyacetophenone derivative with sulfur in the presence of a secondary amine to process a 3-phenoxyphenylacetic acid derivative, condensing the resulting compound with a carbonic acid ester to form an arylmalonic acid ester, introducing an alkyl group into the ester, followed by hydrolysis and decarbonization to obtain the desired compound, as disclosed in Japanese Patent Publication (Examined) No. 45586/76; (2) a process comprising converting a 3-phenoxy-halobenzyl derivative as a starting material into a corresponding cyano compound, then into an alkoxycarbonyl compound, and alkylating, hydrolyzing and decarbonizing the resulting compound in the same manner as described for the process (1) above to obtain the desired compound, as disclosed in Japanese Patent Publication (Examined) No. 45586/76; (3) a process comprising reducing a 3-phenoxyacetophenone derivative followed by halogenation to obtain a 1-(3-phenoxyphenyl)haloethyl, and converting the resulting compound into a corresponding nitrile derivative and then hydrolyzing the nitrile derivative, as disclosed in Japanese Patent Publication (Examined) No. 70744/76; and (4) a process comprising converting the 1-(3-phenoxyphenyl)-haloethyl used in the above process (3) into a Grignard compound and reacting the Grignard compound with carbon dioxide to produce the desired compound, as disclosed in Japanese Patent Publication (Unexamined) No. 65729/76.
However, the above conventional processes are not considered advantageous in the production on an industrial scale for the reasons that these processes require a number of reaction steps to produce the desired compounds; the starting material, an acetophenone derivative, used in the processes (1), (3) and (4) is not easily available as an industrial raw material; a highly toxic hydrocyanic acid derivative must be used as a reagent in the processes (2) and (3); and an absolutely anhydrous condition must be used in preparing the Grignard compound in the process (4).
Also, typical conventional processes for preparing .alpha.-(2-thienyl)alkanoic acid derivatives of the formula (I) wherein A represents a substituted-thienyl group include (1) a process comprising alkylating an .alpha.-(2-thienyl)cyanoacetic acid ester, followed by decarbonization to produce an .alpha.-(2-thienyl)alkanenitrile and then hydrolyzing the nitrile group, as disclosed in M. Bercot-Vatteroni, R. C. Moreau and P. Reynaud Bull. Soc. Chim., France, 1820 (1961); and (2) a process comprising condensing a thiophene with ethyl chloroglyoxarate, and reacting the resulting condensate with a Grignard compound followed by reduction, as disclosed in F. Clemence, O. Le Martret, R. Fournex, G. Plassard and M. Dagnaux, Eur. J. Med. Chem., (1974-9), 390.
However, these processes require a number of complicated reaction steps and therefore cannot be advantageously applied to the production on an industrial scale.